title: KS900: A hypoxia-directed, reductively activated methylating antitumor prodrug that selectively ablates O(6)-alkylguanine-DNA alkyltransferase in neoplastic cells.
abstract: To most effectively treat cancer it may be necessary to preferentially destroy tumor tissue while sparing normal tissues. One strategy to accomplish this is to selectively cripple the involved tumor resistance mechanisms, thereby allowing the affected anticancer drugs to gain therapeutic efficacy. Such an approach is exemplified by our design and synthesis of the intracellular hypoxic cell activated methylating agent, 1,2-bis(methylsulfonyl)-1-methyl-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS900) that targets the O-6 position of guanine in DNA. KS900 is markedly more cytotoxic in clonogenic experiments under conditions of oxygen deficiency than the non-intracellularly activated agents KS90, and 90M, when tested in O(6)-alkylguanine-DNA alkyltransferase (AGT) non-expressing cells (EMT6 mouse mammary carcinoma, CHO/AA8 hamster ovary, and U251 human glioma), and than temozolomide when tested in AGT expressing cells (DU145 human prostate carcinoma). Furthermore, KS900 more efficiently ablates AGT in HL-60 human leukemia and DU145 cells than the spontaneous globally activated methylating agent KS90, with an IC(50) value over 9-fold lower than KS90. Finally, KS900 under oxygen-deficient conditions selectively sensitizes DU145 cells to the chloroethylating agent, onrigin, through the ablation of the resistance protein AGT. Thus, under hypoxia, KS900 is more cytotoxic at substantially lower concentrations than methylating agents such as temozolomide that are not preferentially activated in neoplastic cells by intracellular reductase catalysts. The necessity for intracellular activation of KS900 permits substantially greater cytotoxic activity against cells containing the resistance protein O(6)-alkylguanine-DNA alkyltransferase (AGT) than agents such as temozolomide. Furthermore, the hypoxia-directed intracellular activation of KS900 allows it to preferentially ablate AGT pools under the oxygen-deficient conditions that are present in malignant tissue.
authors.affiliation: Department of Pharmacology and Cancer Center, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520, USA. raymond.baumann@yale.edu
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Baumann
authors.forename: Kimiko
authors.initials: K
authors.lastname: Ishiguro
authors.forename: Philip G
authors.initials: PG
authors.lastname: Penketh
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Shyam
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.forename: Alan C
authors.initials: AC
authors.lastname: Sartorelli
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D008745:Methylation; D051379:Mice; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C559149:1,2-bis(methylsulfonyl)-1-methyl-2-((1-(4-nitrophenyl)ethoxy)carbonyl)hydrazine; D018906:Antineoplastic Agents, Alkylating; D006834:Hydrazines; D011355:Prodrugs; D013449:Sulfonamides; D010088:Oxidoreductases; D019853:O(6)-Methylguanine-DNA Methyltransferase